Valentina Vielmi

The role of mitochondria in neurodegenerative diseases

Mitochondria are implicated in several metabolic pathways including cell respiratory processes, apoptosis, and free radical production. Mitochondrial abnormalities have been documented in neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and amyotrophic lateral sclerosis. Several studies have demonstrated that mitochondrial impairment plays an important role in the pathogenesis of this group of disorders. In this review, we discuss the role of mitochondria in the main neurodegenerative diseases and review the updated knowledge in this field.

High doses of cobalt induce optic and auditory neuropathy.

The adverse biological effects of continuous exposure to cobalt and chromium have been well defined. In the past, this toxicity was largely an industrial issue concerning workers exposed in occupational setting. Nevertheless, recent reports have described a specific toxicity mediated by the high levels of cobalt and chromium released by metallic prostheses, particularly in patients who had received hip implants. Clinical symptoms, including blindness, deafness and peripheral neuropathy, suggest a specific neurotropism. However, little is known about the neuropathological basis of this process, and experimental evidence is still lacking. We have investigated this issue in an experimental setting using New Zealand White rabbits treated with repeated intravenous injections of cobalt and chromium, alone or in combination. No evident clinical or pathological alterations were associated after chromium administration alone, despite its high levels in blood and tissue while cobalt-chromium and cobalt-treated rabbits showed clinical signs indicative of auditory and optic system toxicity. On histopathological examination, the animals showed severe retinal and cochlear ganglion cell depletion along with optic nerve damage and loss of sensory cochlear hair cells. Interestingly, the severity of the alterations was related to dosages and time of exposure. These data confirmed our previous observation of severe auditory and optic nerve toxicity in patients exposed to an abnormal release of cobalt and chromium from damaged hip prostheses. Moreover, we have identified the major element mediating neurotoxicity to be cobalt, although the molecular mechanisms mediating this toxicity still have to be defined.

Pitfalls in diagnosing mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase and is characterized by external ophthalmoparesis, gastrointestinal dysmotility, leukoencephalopathy, and neuropathy. The availability of new therapeutic options (peritoneal dialysis, allogeneic stem cell transplantation, enzyme replacement) makes it necessary to diagnose the disease early, which is not always achieved due to the difficulty in recognizing this disorder, especially in case of atypical presentation. We describe three MNGIE patients with atypical onset of the disease. In the first patient the main symptoms were long-standing chronic fever, recurrent acute migrant arthritis, and gastrointestinal disorders mimicking autoimmune or inflammatory intestinal diseases; the second patient complained only of exercise intolerance and muscle cramps, and the third patient had a CIDP-like polyneuropathy. This study stresses the insidious heterogeneous clinical onset of some cases of MNGIE, expands the spectrum of the phenotype, and suggests considering MNGIE in the differential diagnosis of enteropathic arthritis, isolated exercise intolerance, and inflammatory polyneuropathies not responsive to the usual treatment. A better understanding of the clinical heterogeneity of MNGIE is necessary in order to diagnose atypical cases and promote early diagnosis, which is now absolutely necessary in view of the new available therapies.

Current Options in the Treatment of Mitochondrial Diseases

Mitochondrial diseases (MD) are disorders caused by an impairment of the mitochondrial respiratory chain function. They are usually progressive, isolated or multi-system diseases and have variable times of onset. Because mitochondria have their own DNA (mtDNA), MD can be caused by mutations in both mtDNA and nuclear DNA (nDNA). The complexity of genetic control of mitochondrial function is in part responsible for the intra- and inter-familiar clinical heterogeneity of this class of diseases. Despite the remarkable progress in understanding of the molecular bases of these disorders, therapy of MD is quite inadequate. Present options of treatment mainly include physical, pharmacological and gene therapy approaches. Aerobic exercise and physical therapy is useful to prevent or correct deconditioning and may improve exercise tolerance. Pharmacological approach is based on removing noxious metabolites, using reactive oxygen species scavengers and administrating vitamins and cofactors which is especially important in case of primary deficiencies of specific compounds such as Coenzyme Q10. Gene therapy is fascinating but it is difficult to apply because of polyplasmy and heteroplasmy. Experimental methods include gene shifting, allotopic expression, mitochondrial transfection or correcting mtDNA mutations with specific restriction endonucleases. Here, we discussed some recent patents. Progresses in each of these fields may open interesting perspectives for the future.

Limb-girdle muscular dystrophy-associated protein diseases.

Abstract The limb-girdle muscular dystrophies are a genetically and clinically heterogeneous group of diseases. Most of these proteinopathies show wide inter- and intrafamilial phenotypic heterogeneity, so that limb-girdle involvement may be often considered as one of the possible clinical expressions of a determined protein defect. Review Summary This review reports an updated and comprehensive classification of these proteinopathies according to protein defect and transmission modality and focuses on the main associated clinical pictures. Conclusions An accurate diagnosis is often difficult because of the clinical and genetic variability characterizing this group of muscle diseases. Appropriate diagnostic approaches are essential to achieve the correct diagnosis.

An “inflammatory” mitochondrial myopathy. A case report

We describe a case of an adult male patient with progressive external ophthalmoplegia and upper limb weakness, who presented with an episode of sudden respiratory failure. Muscle biopsy showed ragged-red and COX-negative fibers associated with discrete inflammatory infiltrates and necrotizing features. Apart from artificial ventilator support, he was treated with intravenous immunoglobulins and carnitine, with excellent clinical outcome. Mitochondrial DNA analysis revealed the 3251A>G mutation, previously reported in association with rapidly progressive mitochondrial myopathy and respiratory failure. Our case expands the spectrum of this mutation and suggests a therapeutic attempt with immunoglobulins in mitochondrial patients with acute respiratory failure, at least when this mutation and/or muscle inflammation is present. Moreover, this case supports the idea of a pathologic inflammatory response induced by mitochondrial disease; such an abnormal response may be a contributory factor in disease progression or acute exacerbation typical of some mitochondrial diseases, but further studies are needed.

MR Neurography in Diagnosing Nondiabetic Lumbosacral Radiculoplexus Neuropathy

Here we describe the imaging findings in a 73‐year‐old woman who had pain in the right inguinal region, followed by progressive weakness of muscles innervated by the right femoral and obturator nerves, diagnosed as nondiabetic lumbosacral radiculoplexus neuropathy. Magnetic resonance neurography showed thickening and increase in signal intensity of the right femoral and obturator nerves.

A novel mitochondrial tRNAAla gene variant causes chronic progressive external ophthalmoplegia in a patient with Huntington disease

Chronic progressive external ophthalmoplegia is a mitochondrial disorder usually caused by single or multiple mitochondrial DNA (mtDNA) deletions and, more rarely, by maternally inherited mtDNA point mutations, most frequently in tRNA genes (MTT). We report on a patient presenting with a progressive eyelid ptosis with bilateral ophthalmoparesis, dysphagia, dysphonia and mild proximal limb weakness associate with a mild movement disorder characterized by abnormal involuntary movements involving head and limbs, imbalance and gait instability. Muscle biopsy demonstrated the presence of ragged red fibers and several cytochrome-C-oxidase negative fibers. Molecular analysis showed the novel m.5613T > C heteroplasmic mutation in the mitochondrial tRNAAla gene (MTTA) which disrupts a conserved site and fulfills the accepted criteria of pathogenicity. Moreover, a 38 CAG trinucleotide repeat expansion was found on the huntingtin gene, thus configuring a singular CPEO/“reduced penetrance” Huntington disease “double trouble”. With this novel MTTA point mutation, we extend the spectrum of provisional pathogenic changes in this gene, which is a very rare site of pathogenic mutation, and confirm that clinical expression of these mutations is hardly ever heterogeneous, including myopathy and CPEO. Mitochondrial involvement is an emerging key determinant in the pathogenesis of Huntington disease and it is well known that mutant huntingtin influences the mitochondrial respiratory complexes II and III. A synergist effect of the HTT and MTTA mutations on respiratory chain function may be hypothesized in our patient and should be regarded as a spur for further studies on the mtDNA/HTT reciprocal interactions.

Involvement of the central nervous system myelin in a POEMS patient.

POEMS (polyneuropathy, organomegaly, endocrinopathy, Mrotein and skin changes) syndrome is a rare cause of mixed emyelinating and axonal neuropathy with multi-organ involveent and a monoclonal plasma cell proliferative disorder [1]. ther important traits of the syndrome are sclerotic bone lesions, astleman disease, papilledema, peripheral edema, ascites, effuions, thrombocytosis, polycythemia, clubbing and increased level f the plasmacytomas-secreted vascular endothelial growth factor VEGF) [1]. The pathogenesis is not well understood but a role for VEGF has een suggested [2]. POEMS syndrome is a potentially fatal disease and patients’ uality of life deteriorates because of progressive neuropathy,masive pleural effusion, ascites or thromboembolic events. Cerebral vasculitis, multiple vascular abnormalities, hyperrophic cranial pachymeningitis, bilateral internal carotid rtery occlusion, amyloidosis, diffuse white matter edema and apilledema have been associated with POEMS syndrome [3–8]. n one case, cranial magnetic resonance imaging disclosed diffuse

Hemangioma of the semimembranosus muscle in a patient with late-onset glycogenosis II

no evidence of inflammation (Fig. 1, lower division). The patient’s CMT neuropathy score reached maximum severity (36 of 36), and she was treated again with IVIg with no improvement. Although on insulin, her glycemic control has always been poor, with her HbA1c ranging from 7.7 to 9. The remaining members of her family with CMT had a moderate phenotype, even the older ones. Interestingly, one of her nephews, who had CMT1A and recently diagnosed glucose intolerance, displayed a mild phenotype. Both DM and CMT1A may be complicated by an associated acquired inflammatory neuropathy, which changes the typical course of these diseases. In this case, the absence of an inflammatory infiltrate on the nerve biopsy, the lack of improvement after two IVIg courses, and the length-dependent distribution of her manifestations did not support this possibility. As no other inflammatory, infectious, or toxic conditions were found, it is possible that the severity of her neuropathy resulted from the combined effect of both conditions, DM and CMT1A, suggesting that the entire clinical spectrum of this association has not yet been described. As DM is a manageable disease, earlier and efficient interventions may have lessened the severity of the neuropathy that subsequently developed. This work was funded by FAPESP, CAPES, CNPq, FAPESP, and INCT Translational Medicine, Brazil. We thank Mrs. Sandra E. Marques and Renato Meireles for skillful technical work.